The therapy of tumours is being currently achieved by surgical intervention, radiation treatment and chemotherapy. The drawbacks of this latter are mainly due to the toxicity of the cytotoxic drugs, which is usually not limited to the cancer cells, and to the acquired resistance of the cancer cells to some of the most widely used drugs, which reduces the long-term efficacy of the therapy.
The elimination of the primary tumour by surgery is not always possible and in any case does not prevent the most metastasizing tumours, such as for example breast cancer or melanoma, to invade other target organs.
It has become evident that the therapy of the metastasizing tumours is unlikely to bring to the complete cure of the patient; therefore, the treatment with cytotoxic drugs is now seen as a palliative and life-prolonging method rather than a curative method. A chronic treatment with a drug having low toxicity would be preferable, while targeted to the control of the progression of the disease.
During the last years cancer drug development has moved from conventional cytotoxic chemotherapeutics to a more mechanism-based targeted approach towards the common goal of tumour growth arrest. The rapid progress in chromatin research and understanding epigenetic control has supplied a plethora of potential targets for intervention in cancer.
Histone deacetylases (HDACs) have been widely implicated in growth and transcriptional control, and inhibition of HDAC activity using small molecules causes apoptosis in tumour cells. Histone deacetylase inhibitors are now known to be potent inducers of growth arrest, differentiation, or apoptotic cell death in a variety of transformed cells in culture and in tumour bearing animals (Marks, P. A., Current Opinions in Oncology, 2001, Nov. 13 (6): 477-83; Marks, P., Nat. Rev. Cancer 2001 Dec. 1 (3):194-202).
On the other hand, as anticipated before, another very important and keenly perceived aspect of oncological therapy is the onset of resistance to the drug used by the tumour cells treated. The cells that develop resistance to a drug are often capable of resisting the effects of many other antitumour drugs, even if these are unrelated chemically or act with different mechanisms of action. (Annu. Rev. Med. 1991, 42: 277-286; Drugs of the Future 1997, 22: 653-660).
A number of tumours, such as, for instance, tumours of the adrenal cortex, colon, kidneys and jejunum and liver carcinoma manifest drug resistance right from the very start of treatment with antitumour drugs (Barrows, L. R. Antineoplastic and Immunoactive Drugs, 1995; 75; 1236-1262).
In other cases, the tumour cells acquire resistance in a manner similar to that of bacterial resistance to antibiotics. This type of resistance has genetic or epigenetic changes; these changes allow the daughter cells to proliferate in a milieu in which the antitumour agent is present.
Whatever the cause of the resistance, it leads to inefficacy of the antineoplastic treatment in the long term.
Patent application WO99/00381 describes bis-indole derivatives with antimetastatic activity.
Patent application WO02/36561, filed in the name of the applicant discloses compounds bis-heterocyclic compounds useful as antitumour agents.
In conclusion, in the oncology field there is a strongly perceived need for new compounds endowed with antitumour and/or chemosensitising activity, i.e. compounds which are active against drug-resistant tumours and/or capable of making known antitumour drugs active against tumours against which they were ineffective owing to the onset of the above-mentioned conditions of drug resistance.